Summary: A large genetic study indicates that a low body mass index (BMI) is unlikely to be a causal factor in developing Alzheimer’s disease.
Source: Endocrine Society.
Research clarifies the link between weight and the common form of dementia
A new, large-scale genetic analysis finds that low body mass index (BMI) does not appear to cause Alzheimer’s disease, contradicting earlier observational studies that suggested a direct link. The research, published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism, used genetic methods to separate correlation from causation.
“Previous studies reported an association between Alzheimer’s disease and lower BMI, but our results indicate this relationship is not causal,” said senior author Ruth Frikke-Schmidt, M.D., D.M.Sc., Ph.D., Chief Physician at Rigshospitalet in Copenhagen and Associate Research Professor at the University of Copenhagen. “Lower BMI in people who later develop dementia is more likely a consequence of preclinical disease—early appetite loss and weight decline—rather than a factor that increases disease risk.”
Alzheimer’s disease affects millions worldwide and is a leading cause of dementia and mortality in older adults. To investigate whether low BMI itself raises Alzheimer’s risk, the researchers applied a Mendelian randomization approach, which uses genetic variants associated with a trait as natural experiments to test causality.
The core analysis examined blood and DNA from 95,578 participants in the Copenhagen General Population Study (CGPS), among whom 645 developed Alzheimer’s disease over follow-up. The team screened participants for five genetic variants strongly linked to BMI and grouped individuals by the number of BMI-decreasing alleles they carried, reflecting lifelong predisposition to lower body weight. The investigators also evaluated genetic data from up to 249,796 people in the Genetic Investigation of Anthropometric Traits (GIANT) consortium to validate associations with lower BMI.
The genetic analysis showed no increase in Alzheimer’s risk among people with genetic markers for lifelong lower BMI. As a positive control, the researchers confirmed that genetic variants tied to higher BMI did predict a greater risk of type 2 diabetes, demonstrating that the Mendelian randomization approach could detect known causal relationships.
“Individuals with genetically lower BMI throughout life were not at higher risk of Alzheimer’s disease,” Frikke-Schmidt explained. “Because inherited genetic variants are determined at conception and are not biased by lifestyle or disease-related changes, they provide a robust test of causality. Our findings emphasize the importance of testing whether observational risk factors truly cause disease before changing public health recommendations.”
Other authors include Liv Tybjærg Nordestgaard, Anne Tybjærg-Hansen, and Børge G. Nordestgaard, all affiliated with Rigshospitalet, Herlev and Gentofte Hospital, and the University of Copenhagen.
Funding: The research received support from the Danish Medical Research Council, the Lundbeck Foundation, the Alzheimer Research Foundation, and the Research Fund at the Capital Region of Denmark.
Source: Jenni Glenn Gingery – Endocrine Society
Image Source: NeuroscienceNews.com image (public domain)
Original Research: Abstract for “Body Mass Index and Risk of Alzheimer Disease: a Mendelian Randomization Study of 399,536 Individuals” by Liv Tybjærg Nordestgaard, Anne Tybjærg-Hansen, Børge G. Nordestgaard, and Ruth Frikke-Schmidt, Journal of Clinical Endocrinology & Metabolism. Published online May 9, 2017. doi:10.1210/jc.2017-00195
Endocrine Society (2017). Study Finds Alzheimer’s Disease Likely Not Caused by Low Body Mass Index. NeuroscienceNews. Published May 9, 2017.
Abstract
Body Mass Index and Risk of Alzheimer Disease: a Mendelian Randomization Study of 399,536 Individuals
Context: Large observational datasets have reported that lower body mass index (BMI) is associated with higher dementia risk. It has remained unclear whether lower BMI directly increases Alzheimer’s disease risk or whether the association reflects reverse causation or confounding.
Objective: To determine whether genetically determined lower BMI causally increases the risk of Alzheimer’s disease.
Design, Setting and Participants: Using Mendelian randomization, the study analyzed 95,578 people from the Copenhagen General Population Study (CGPS) with up to 36 years of follow-up, and consortia data from GIANT and the International Genomics of Alzheimer’s Project (IGAP), totaling 399,536 individuals.
Main Outcome Measure: Risk of Alzheimer’s disease.
Results: In the CGPS, the causal odds ratio for a 1 kg/m2 genetically lower BMI was 0.98 (95% CI: 0.77–1.23) using a weighted allele score. Using 32 BMI-decreasing variants from GIANT and IGAP, the causal odds ratio for Alzheimer’s disease per one standard deviation lower genetically determined BMI was 1.02 (95% CI: 0.86–1.22). Observational hazard ratios in the CGPS for the same BMI reductions were higher, indicating the observational association likely reflects reverse causation or confounding.
Conclusions: Lifelong genetically lower BMI is not associated with increased Alzheimer’s disease risk in the general population. Observational links between low BMI and dementia are likely explained by reverse causation or other confounding factors rather than a direct causal effect.